CN1053667C - Inhibitng photodecomposition of 3-substituted-2-oxindoles - Google Patents
Inhibitng photodecomposition of 3-substituted-2-oxindoles Download PDFInfo
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- CN1053667C CN1053667C CN96105084A CN96105084A CN1053667C CN 1053667 C CN1053667 C CN 1053667C CN 96105084 A CN96105084 A CN 96105084A CN 96105084 A CN96105084 A CN 96105084A CN 1053667 C CN1053667 C CN 1053667C
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- thienyl
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- 238000006303 photolysis reaction Methods 0.000 title claims description 16
- -1 3-substituted-2-oxindoles Chemical group 0.000 title abstract description 9
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 22
- 239000001043 yellow dye Substances 0.000 claims description 21
- 239000002775 capsule Substances 0.000 claims description 18
- AJDUTMFFZHIJEM-UHFFFAOYSA-N n-(9,10-dioxoanthracen-1-yl)-4-[4-[[4-[4-[(9,10-dioxoanthracen-1-yl)carbamoyl]phenyl]phenyl]diazenyl]phenyl]benzamide Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2NC(=O)C(C=C1)=CC=C1C(C=C1)=CC=C1N=NC(C=C1)=CC=C1C(C=C1)=CC=C1C(=O)NC1=CC=CC2=C1C(=O)C1=CC=CC=C1C2=O AJDUTMFFZHIJEM-UHFFFAOYSA-N 0.000 claims description 17
- 238000000576 coating method Methods 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 13
- 230000015843 photosynthesis, light reaction Effects 0.000 claims description 13
- 239000011358 absorbing material Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000000975 dye Substances 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 150000002085 enols Chemical class 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 8
- 238000000354 decomposition reaction Methods 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 102000000589 Interleukin-1 Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- 239000000326 ultraviolet stabilizing agent Substances 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical class C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- PBJMXECUDJZEFZ-UHFFFAOYSA-N 6-chloro-2-oxo-1h-quinazoline-4-carboxylic acid Chemical compound C1=C(Cl)C=C2C(C(=O)O)=NC(=O)NC2=C1 PBJMXECUDJZEFZ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 239000004218 Orcein Substances 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 230000010748 Photoabsorption Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000019248 orcein Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000004901 spalling Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4883—Capsule finishing, e.g. dyeing, aromatising, polishing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
This invention relates to the protection of certain 3-substituted-2-oxindole-1-carboxamides of formula below and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl, each optionally substituted with Cl or F from decomposition in the presence of light.
Description
The present invention relates to suppress some 3-of following formula replaces-photolysis of the subsalt that 2-oxindole-1-methane amide and medicine thereof are allowed.
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also can be replaced by Cl or F.
U.S.4569942 discloses the 2-oxindole-1-methane amide of some following formulas
X is H, F, Cl, Br, C in the formula
1～C
4Alkyl, C
3～C
7Cycloalkyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylthio, trifluoromethyl, C
1～C
4Alkyl sulfinyl, C
1～C
4Alkyl sulfide acyl group, nitro, phenyl, C
2～C
4Alkyloyl, benzoyl, Thenoyl, C
1～C
4Alkyl amido, benzamido or each described alkyl have the N of 1～3 carbon, N-dialkyl sulfamine; Y is H, F, Cl, Br, C
1～C
4Alkyl, C
3～C
7Cycloalkyl, C
1～C
4Alkoxyl group, C
1～C
4Alkylthio and trifluoromethyl; R
1Be C
1～C
6Alkyl, C
3～C
7Cycloalkyl, C
4～C
7Cycloalkenyl group, phenyl, substituted-phenyl, described alkyl have the benzene alkyl of 1～3 carbon, described alkyl have (substituted-phenyl) alkyl of 1～3 carbon, described alkyl have (substituent phenoxy) alkyl of 1～3 carbon, described alkyl have 1～3 carbon (thiophene oxy) alkyl, naphthyl, dicyclo (2.2.1) heptane-2-base, dicyclo (2.2.1) heptan-5-alkene-2-base or-(CH
2)
n-Q-R; N is 0,1 or 2; Q is by furans, thiophene, pyrroles, pyrazoles, imidazoles, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazoles, 1,3,4-thiadiazoles, 1,2, the divalent radical that 5-thiadiazoles, tetrahydrofuran (THF), tetramethylene sulfide, tetrahydropyrans, tetrahydric thiapyran, pyridine, phonetic azoles, pyrazine, benzo (b) furans and benzo (b) thiophene obtain; R
2Be C
1～C
6Alkyl, C
3～C
7Cycloalkyl, benzyl, furyl, thienyl, pyridyl or
R wherein
3And R
4Be H, F, Cl, C
1～C
4Alkyl, C
1～C
4Alkoxyl group or trifluoromethyl.This patent is also open, and described 2-oxindole-1-methane amide is the inhibitor of cyclooxygenase and lipoxygenase, and it has analgesic activity in Mammals, and is used for the treatment of pain and the misery that alleviates the chronic disease symptom.
U.S.4556672 discloses the 2-oxindole-1-methane amide of the 3-acyl substituted of some following formula.
X, Y and R describe as the compound of above-mentioned US4569942 in the formula.
US4861794 discloses the subsalt that following formula: compound and medicine thereof allow and has been used to suppress the biosynthesizing of interleukin-1 (IL-1) and mediated disorders and the dysfunction of treatment IL-1,
X is H, Cl or F in the formula, and Y is H or Cl, and R is benzyl or thienyl.
The present invention relates to a kind of method that suppresses the photolysis of the salt that formula 1 compound and enol form compound or its medicine thereof allow,
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each all can be replaced by Cl or F; Described photolysis is caused that by the light of light emitted this method is included between described compound and the described light source and introduces light absorbing material.
In a preferred method of the invention, described light absorbing material is a kind of yellow dye that is selected from
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3 dyestuff.
In another preferred method of the present invention, described light absorbing material is a yellow dye
#6.
On the other hand, the present invention relates to a kind of tablet that contains the effective ingredient that is selected from the subsalt that following formula: compound or its medicine allow,
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also available Cl or F replace; Described tablet scribbles and contains the sufficient amount yellow dye
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3 coating is to suppress the photolysis of described effective ingredient.
One preferred aspect in, the present invention includes once the tablet that applies, wherein said coating contains the yellow dye of sufficient amount
#6, to suppress the photolysis of described effective ingredient.
In aspect another is preferred, the present invention includes a capsule, it contains the effective ingredient that is selected from the subsalt that following formula: compound or its medicine allow,
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also available Cl or F replace; Described capsule shell contains the sufficient amount yellow dye
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3, to suppress the photolysis of described effective ingredient.
The compound of following formula is disclosed in U.S.4556672 and 5290802
And enol formalization compound
The subsalt of allowing with medicine and the preparation method of above-claimed cpd matter, wherein X is H, Cl or F; Y is H or Cl; R is benzyl or thienyl, and each available Cl or F replace.The disclosure of these patents is incorporated the present invention here as a reference into.Found that these compounds, can be by photolysis to only responsive.The present invention relates to by stoping light to contact the method for the photolysis that prevents formula I compound and enol formalization compound thereof with described compound.
The term of Shi Yonging " light source " refers to sunlight or any artificial light that can produce wavelength less than 600 nanometer light in the present invention." light absorbing material " refers to shield material such as the dense glass or the metal of light all or most of wavelength; Perhaps can absorb material such as ultra-violet stabilizer or dyestuff less than 600 nano wave length light.
The photoabsorption material can be used for wrapping material such as foldable bag, sachet or bottle.Chemical light absorbing material such as ultra-violet stabilizer can be added in the wrapping material that comprise foldable bag, sachet or bottle, perhaps preferably are added in capsule shell or the tablet coating.The chemical light absorbing material directly mixes with effective constituent before also can or putting into capsule shell in film-making.
" inhibition photolysis " refers to statistically significantly to reduce the generation of the degraded product that the light that is described below causes.
In the method for the inhibition photolysis that is described below, preferably such certain methods, use therein compound is the compound of above-mentioned formula I; Wherein X is Cl, and Y is H, and R is the compound of thiophene base; Wherein X is F, and Y is Cl, and R is the compound of thienyl or 4-chloro-thiophene-2-base; Wherein X is that F, Y are that Cl, R are the compound of 2-thienyl; And wherein X is that H, Y are that Cl, R are the compound of benzyl.Particularly preferably be wherein that X is Cl, Y is H, and R is the method for 2-thienyl.Formula I compound can the enol form exist; All such enol form and salt thereof all comprise in the present invention.
As disclosed in US4556672 and 5290802, the compound of the present invention's protection is the subsalt of acidic cpd and generation.All such subsalt all can be made by the content of these patent disclosures all within the scope of the present invention.These salt that are suitable for comprise organic salt and inorganic salt within the scope of the present invention, comprising but be not limited to the salt that generates with ammonia, organic amine, alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, alkalimetal hydride, alkali metal alkoxide, alkaline earth metal hydroxides, alkaline earth metal carbonate, alkaline earth metal hydride and alkaline-earth metal alkyl oxide.The example that generates the representative alkali of these subsalt comprises ammonia; Primary amine is as Tri N-Propyl Amine, n-Butyl Amine 99, aniline, hexahydroaniline, benzylamine, para-totuidine, thanomin and glycosamine; Secondary amine is as diethylamine, diethanolamine, N-methylglucosamine, methylphenylamine, morpholine, tetramethyleneimine and piperidines; Tertiary amine, as triethylamine, trolamine, N, accelerine, N-ethylpiperidine and N-methylmorpholine; Oxyhydroxide is as sodium hydroxide; Alkoxide is as sodium ethylate and potassium methylate; Hydride is as hydrolith and sodium hydride; Carbonate is as salt of wormwood and yellow soda ash.Preferred salt is the salt of sodium, potassium, ammonium, thanomin, diethanolamine and trolamine.Particularly preferably be sodium salt.Compounds suitable for use of the present invention comprises solvate; Semihydrate and monohydrate as above-mentioned compound.
The degraded of oxindole-1-methane amide that the 3-that light causes replaces mainly appears at optical wavelength less than under 600 nanometers, and the main degradation production of generation is phenylformic acid or thiophenic acid and oxindole-1-methane amide.Can avoid this degraded less than the light of 600 nanometers with the method that oxindole-the 1-methane amide contacts that 3-replaces by stoping wavelength.
Found that orchil is being effective with yellow dyes aspect the degraded of the oxindole-1-methane amide that stops the 3-replacement that light contacts and relevant light causes.Preferred dyestuff is FD﹠amp; The C red
#40, FD﹠amp; The C red
#3 and FD﹠amp; The C yellow dye
#6.Yellow dye
#The 6th, particularly preferred.When these dyestuffs and oxindole mix or be coated in when becoming coating on the ready-formed tablet or being added in the gelatine capsule that oxindole is housed, they are being effective aspect the oxindole-1-methane amide degraded of the 3-replacement that stops light to cause.Preferable methods is the coating of tablet.
The film coating of medicinal tablet is that everybody is familiar with in the art, for example describes in US4828841,3981948 and 3802896, and here they incorporate the present invention as a reference into.Be applicable to film coating material such as White Opadry, Opadry ll, Sutelease, Aquacoat and the Eudragit of selected dye formulation can be respectively from Colorcon, WestPoint, PA; FMC Corp., Philadelphia, PA; Rohm Pharma, Weitter-stadt, Germany is purchased.
These dyestuffs also can be filled a prescription in gelatine capsule, in then oxindole being incapsulated.To those skilled in the art, making capsular technology is that everybody is familiar with.The capsule that is added with selected dyestuff can be by Elanco Shinogi, Iudianapolis, and IN and Capsug-el, Greeuwood, SC is purchased.US3784684 discloses opalizer and dyestuff is added in the gelatine capsule shell.
Except that adding enough dyestuffs to absorb any light of injecting, the quantity of dyestuff in coating or capsule shell is inessential.We find, 1.2～2.8 milligrams of yellow dyes
#6/ can prevent to decompose, and 0.28～0.5 milligram/capsule can provide light stability in capsule shell.
The representative formula of coated tablet of the present invention can be prepared as follows:
Component milligram/sheet
Light indoles-1-acid amides 21.74
Klucel EF 6.00
Lactose, anhydrous 122.26
Ac-Di-Sol 6.00
Avicel PH102 40.00
Magnesium Stearate 3.60
Lauryl sulfate sodium salt 0.40
Gross weight (core) 200.00
White Opadry(YS-5-7068)
a 10.00
Distilled water
Yellow lake
*6 (39% purity)
b1.15
Gross weight (thin film coated sheet) 211.15
aThe thin film coated group
bContain dye set
Following examples are used for illustrating the present invention, rather than are used for limiting the present invention, and the present invention is defined by the claims.
Embodiment 1
The tablet of coating
Make 5-chloro-2 with above-mentioned prescription, the tablet cores of 3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-methane amide (600 gram).
To contain available from Colorcon, West Point, PA contains yellow dye
#6 OrangeOpadry (144 gram) is suspended in 816 ml waters.Tablet cores is packed in Hi CoaterHCT 30 coating machines, and remain under 42 ℃, simultaneously Orange Opadry suspension is coated.
With two batches of coatings and 5-chloro-2 a collection of not coating, (Y=H) tablet is heated to 30 ℃ and 50 ℃ to 3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-methane amide for formula I, X=Cl, and places for 6 weeks in the light cupboard.All tablet cores of three batches are identical.The unique difference of coated tablet is a yellow dyes in the film coating
#6 quantity.The intensity at light cupboard center is 400 ft-cs (FC), and the intensity around the light cupboard is 300FC, and the light cupboard keeps at room temperature.
Outward appearance at 30 ℃ and the 50 ℃ samples of storing down is as broad as long with the outward appearance of the sample of storing down at 5 ℃, does not all observe the surfacial spalling of film coating for all tablets.Carry out following range estimation in the light cupboard, storing the sample in 6 weeks:
The 1st batch (core) is black slightly, brown macules (comparing with 5 ℃ of contrast samples)
The 2nd batch (coating) fade slightly (with 5 ℃ the contrast samples compare)
The 3rd batch (coating) be armpit look (comparing with 5 ℃ of contrast samples) slightly
This LC evaluation result of three batches is compiled in following table.All samples are all pressed triplicate the analysis.The evaluation of estimate of uncoated tablet agent is near 100 milligrams that estimate/gram.For the tablet that does not have coating; in the light cupboard, (compare) thiophene-2-carboxylic acid, 6-chloro-1H-quinazoline-2 with 5 ℃ of contrast samples; 4-diketone, thiophene-2-carboxylic acid 1-formamyl-5-chloro-2-oxo-2,3-dihydro 1H-indol-3-yl ester, 6-chloro-2-hydroxyl-quinazoline-4-carboxylic acid and unknown material
#3 content has increase slightly.Do not observe tangible degraded for the tablet cores of under 5 ℃, 30 ℃ and 50 ℃, storing.
5 ℃, 30 ℃ and 50 ℃ down or the coated tablet of in the light cupboard, storing do not observe tangible degraded.After 6 weeks, for the tablet of two batches of coatings, the palliating degradation degree of sample is roughly the same in the light cupboard.The result of above-mentioned test lists following table in.
Embodiment 2
| 40 milligrams of 5-chloro-2.3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) stability, 6 weeks * | ||||
| 1 group (label) | ||||
| 6 weeks: | 5℃ | 30℃ | 50℃ | LC |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 39.4 | 39.7 | 39.8 | 38.7 |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 99.0 | 99.8 | 100.8 | 97.8 |
| The % thiophene-2-carboxylic acid | 0.01 | 0.02 | 0.04 | 0.28 |
| %6-chloro-1H-quinazoline-2, the 4-diketone | ND | ND | ＜0.01 | 0.06 |
| % thiophene-2-carboxylic acid 1-formamyl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl ester | 0.01 | 0.03 | 0.02 | 0.19 |
| %6-chloro-2-carboxyl-quinazoline-4-carboxylic acid | 0.01 | 0.03 | 0.04 | 0.29 |
| % unknown material #3 ** | ND | ND | ND | 0.03 |
| 2 groups of (coated foil, 1.35 milligrams of yellow dyes #6) | ||||
| 6 weeks: | 5℃ | 30℃ | LC | |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 39.5 | 39.4 | 38.7 | |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 92.7 | 93.1 | 91.2 | |
| The % thiophene-2-carboxylic acid | 0.02 | 0.01 | 0.03 | |
| %6-chloro-1H-quinazoline-2, the 4-diketone | 0.02 | 0.02 | 0.02 | |
| % thiophene-2-carboxylic acid 1-formamyl-5-chloro-2-oxo-2,3-dihydro-indol-3-yl ester | 0.01 | 0.01 | 0.01 | |
| %6-chloro-2-carboxyl-quinazoline-4-carboxylic acid | 0.03 | 0.02 | 0.04 | |
| 3 groups of (coated foil, 0.9 milligram of yellow dye #6) | ||||
| 6 weeks | 5℃ | 30℃ | 50℃ | LC |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2-thienyl methene)-2-oxo-1H-indoles-1-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 39.5 | 39.6 | 39.0 | 39.0 |
| 5-chloro-2,3-dihydro-3-(hydroxyl-2 thienyl methene)-2-oxo-lH-indoles-l-acid amides (formula I, X=Cl, Y=H) (milligram/sheet) | 94.9 | 94.8 | 94.3 | 93.3 |
| The % thiophene-2-carboxylic acid | 0.01 | 0.03 | 0.04 | 0.04 |
| %6-chloro-1H-quinazoline-2, the 4-diketone | 0.01 | 0.01 | 0.01 | 0.01 |
| % thiophene-2-carboxylic acid 1-formamyl-5-chloro-2-oxo-2,3-dihydro 1H-indol-3-yl ester | 0.01 | 0.02 | 0.02 | 0.02 |
| %6-chloro-2-carboxyl-quinazoline-4-carboxylic acid | 0.02 | 0.04 | 0.05 | 0.05 |
| *Stability to 5 ℃ of contrast samples compares number | ||||
| **Area percent | ||||
By the prescription of following component preparation I compound, wherein X is Cl, and Y is H, and R is a thienyl:
Milligram/unit
Formula I sodium type compound 128.205
Lactose, anhydrous 159.795
Pregelatinised starch 112.500
Croscormellose Sodium 9.000
Magnesium Stearate 9.000
Mentioned component is mixed, and a part of roll extrusion is solid, grind with all the other compositions then and admix again, lubricated and enclose available from Capsugel, in the gelatine capsule of a division of Warner-Lambert Com-pany.Preferred lubricant is the lauryl sulfate sodium salt.The 0.2651%FD﹠amp that in capsule body, contains the butt gross weight; C yellow dye and in capsule cap, contain 0.1768%FD﹠amp; The C yellow dye.
Find that the capsule that makes with this method has light stability to formula I compound.
Claims (14)
1. one kind is suppressed the method that following formula: compound and enol formalization compound or medicine thereof are allowed the subsalt photolysis
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also available Cl or F replace; Light by light emitted causes described photolysis, and this method is included between described compound and the described light source and introduces light absorbing material.
2. according to the process of claim 1 wherein that X is Cl; Y is H; R is a thienyl.
3. according to the method for claim 2, wherein R is the 2-thienyl.
4. according to the method for claim 3, the subsalt that its Chinese traditional medicine is allowed is a sodium salt.
5. according to the process of claim 1 wherein that X is F; Y is Cl; R is thienyl or 4-chlorothiophene-2-base.
6. according to the method for claim 5, wherein R is 4-chlorothiophene-2-base.
7. according to the process of claim 1 wherein that X is H; Y is Cl; R is a benzyl.
8. according to the process of claim 1 wherein that described light absorbing material is to be selected from yellow dye
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3 dyestuff.
9. method according to Claim 8, wherein said light absorbing material is a yellow dye
#6.
10. tablet that contains the effective ingredient that is selected from the subsalt that following formula: compound or its medicine allow,
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also available Cl or F replace; Described tablet is with containing the sufficient amount yellow dye
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3 coating applies, to suppress the photolysis of described effective ingredient.
11. according to the tablet of claim 10, wherein said coating contains yellow dye
#6.
12. a capsule that contains the effective ingredient that is selected from the subsalt that following formula: compound or its medicine allow,
X is H, Cl or F in the formula; Y is H or Cl; R is benzyl or thienyl, and each also available Cl or F replace; Described capsule shell contains the yellow dye of sufficient amount
#6, red
#40, red
#3, yellow lake
#6, the red shallow lake
#40 and red the shallow lake
#3, to suppress the photolysis of described effective ingredient.
13. according to the capsule of claim 12, wherein said shell contains yellow dye
#6.
14. according to the process of claim 1 wherein that described light absorbing material is the effective wrapping material of absorb light.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB1995/000287 WO1996033701A1 (en) | 1995-04-24 | 1995-04-24 | Inhibiting photodecomposition of 3-substituted-2-oxindoles |
| WOPCT/TB95/00287 | 1995-04-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1139110A CN1139110A (en) | 1997-01-01 |
| CN1053667C true CN1053667C (en) | 2000-06-21 |
Family
ID=36997502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96105084A Expired - Fee Related CN1053667C (en) | 1995-04-24 | 1996-04-22 | Inhibitng photodecomposition of 3-substituted-2-oxindoles |
Country Status (30)
| Country | Link |
|---|---|
| EP (1) | EP0827399A1 (en) |
| JP (1) | JPH10506635A (en) |
| KR (1) | KR100189585B1 (en) |
| CN (1) | CN1053667C (en) |
| AP (1) | AP607A (en) |
| AR (1) | AR002728A1 (en) |
| AU (1) | AU692378B2 (en) |
| BG (1) | BG100531A (en) |
| BR (1) | BR9602024A (en) |
| CO (1) | CO4700418A1 (en) |
| FI (1) | FI973988A0 (en) |
| HR (1) | HRP960194A2 (en) |
| HU (1) | HU216544B (en) |
| IL (1) | IL117969A0 (en) |
| IS (1) | IS4339A (en) |
| MA (1) | MA23848A1 (en) |
| NO (1) | NO961622L (en) |
| NZ (1) | NZ286432A (en) |
| OA (1) | OA10286A (en) |
| PE (1) | PE34397A1 (en) |
| RO (1) | RO113305B1 (en) |
| RU (1) | RU2109510C1 (en) |
| SG (1) | SG64924A1 (en) |
| SI (1) | SI9600133A (en) |
| SK (1) | SK51296A3 (en) |
| TR (1) | TR199600300A2 (en) |
| UA (1) | UA42739C2 (en) |
| WO (1) | WO1996033701A1 (en) |
| YU (1) | YU25096A (en) |
| ZA (1) | ZA963210B (en) |
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|---|---|---|---|---|
| JP2021510067A (en) | 2017-12-29 | 2021-04-15 | クラフト・フーズ・グループ・ブランズ・エルエルシー | Improved oxidative stability of oil-in-water emulsions using natural stabilizers |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2246072A (en) * | 1990-07-20 | 1992-01-22 | Egyt Gyogyszervegyeszeti Gyar | Pharmaceutical compositions stabilised against light |
| WO1994007488A1 (en) * | 1992-10-07 | 1994-04-14 | Pfizer Inc. | 3-substituted 2-oxindole-1-carboxamide pharmaceutical compositions |
-
1995
- 1995-04-24 UA UA96041574A patent/UA42739C2/en unknown
- 1995-04-24 WO PCT/IB1995/000287 patent/WO1996033701A1/en not_active Application Discontinuation
- 1995-04-24 EP EP95914494A patent/EP0827399A1/en not_active Ceased
- 1995-04-24 JP JP8532298A patent/JPH10506635A/en active Pending
- 1995-04-24 RU RU96108120A patent/RU2109510C1/en active
- 1995-04-24 SK SK512-96A patent/SK51296A3/en unknown
-
1996
- 1996-03-07 AP APAP/P/1996/000787A patent/AP607A/en active
- 1996-03-28 AR ARP960101956A patent/AR002728A1/en unknown
- 1996-04-10 TR TR96/00300A patent/TR199600300A2/en unknown
- 1996-04-18 IL IL11796996A patent/IL117969A0/en unknown
- 1996-04-19 SG SG1996009306A patent/SG64924A1/en unknown
- 1996-04-19 IS IS4339A patent/IS4339A/en unknown
- 1996-04-22 CO CO96019210A patent/CO4700418A1/en unknown
- 1996-04-22 CN CN96105084A patent/CN1053667C/en not_active Expired - Fee Related
- 1996-04-22 PE PE1996000275A patent/PE34397A1/en not_active Application Discontinuation
- 1996-04-22 RO RO96-00843A patent/RO113305B1/en unknown
- 1996-04-23 NZ NZ286432A patent/NZ286432A/en unknown
- 1996-04-23 BG BG100531A patent/BG100531A/en unknown
- 1996-04-23 NO NO961622A patent/NO961622L/en unknown
- 1996-04-23 ZA ZA9603210A patent/ZA963210B/en unknown
- 1996-04-23 KR KR1019960012356A patent/KR100189585B1/en not_active IP Right Cessation
- 1996-04-23 HU HU9601057A patent/HU216544B/en not_active IP Right Cessation
- 1996-04-23 YU YU25096A patent/YU25096A/en unknown
- 1996-04-23 AU AU50851/96A patent/AU692378B2/en not_active Ceased
- 1996-04-23 MA MA24209A patent/MA23848A1/en unknown
- 1996-04-23 HR HRPCT/IB95/00287A patent/HRP960194A2/en not_active Application Discontinuation
- 1996-04-24 BR BR9602024A patent/BR9602024A/en active Search and Examination
- 1996-04-24 SI SI9600133A patent/SI9600133A/en not_active IP Right Cessation
- 1996-04-24 OA OA60821A patent/OA10286A/en unknown
-
1997
- 1997-10-17 FI FI973988A patent/FI973988A0/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2246072A (en) * | 1990-07-20 | 1992-01-22 | Egyt Gyogyszervegyeszeti Gyar | Pharmaceutical compositions stabilised against light |
| WO1994007488A1 (en) * | 1992-10-07 | 1994-04-14 | Pfizer Inc. | 3-substituted 2-oxindole-1-carboxamide pharmaceutical compositions |
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